Maron-Gutierrez, T. | bioRxiv Science

bioRxiv2025

Lipid Nanoparticle Delivery of Mesenchymal Stromal Cell-Derived microRNA 187-3p as a First-in-Class Therapy for Myocardial Dysfunction in Sepsis

BackgroundSepsis-induced myocardial dysfunction is a common and critical complication of sepsis. Extracellular vesicles (EVs) from clonally expanded immortalized mesenchymal stromal cells (ciMSCs) contain microRNAs that may be exploited as therapy. MethodsIn mouse models of septic cardiomyopathy induced by caecum ligation and puncture, cardiac function was determined by invasive and echocardiographic assessment. Primary cardiomyocytes derived from foetal murine and human adult ventricular tissue, as well as murine hearts were used for mechanistic studies. Studies using post-mortem human hearts or patient plasma, and clinical and echocardiographic measurements were used to establish translational relevance. ResultsIn preclinical models of sepsis, intravenous administration of either MSCs or ciMSC-EVs, given after the induction of sepsis, prevented a decrease in myocardial ejection fraction, ventricular inflammation, and mortality compared to placebo or platelet-derived control EVs. EV-microRNA sequencing identified enrichment for microRNA-187a-3p (miR-187) in ciMSC-EVs. miR-187 is anti-inflammatory; with interleukin-6 (IL-6) as its major target. Intravenous delivery of lipid nanoparticle (LNP) encapsulated miR-187 improved cardiac function, reduced inflammation, and enhanced survival of septic mice. In cardiomyocytes and in murine hearts, LNP-miR-187 reduces inflammation and expression of myocardial transcription factors linked to fetal gene reactivation in failing septic hearts. In human septic hearts, low circulating miR-187 levels correlate with reduced cardiac function and high sequential organ failure assessment (SOFA) scores. ConclusionThese findings support the development of first-in-class, cell-free, miRNA-based therapy as a novel approach to treat sepsis-induced cardiomyopathy to address a critical gap in sepsis care. One Sentence SummarymiR-based therapy for sepsis The Clinical PerspectiveA. What is NEW? Sepsis accounts for 1 in 5 deaths worldwide. Here, we demonstrate that sepsis-induced myocardial dysfunction represents a discrete, targetable sepsis-trait -- a distinct biological abnormality characterized by cardiomyocyte inflammation and fetal gene reactivation. This component contributes to the propagation of organ dysfunction and overall mortality and may respond to focused epigenetic-based interventions. B. What are the Clinical implications? Currently, there are no effective treatments to reduce, limit, or reverse the immune dysfunction component of sepsis that contributes to multiorgan failure, such as sepsis-induced cardiomyopathy. We identify miR-187 as a clinically relevant post-transcriptional regulator of cardiac inflammation and cardiomyocyte gene expression. Intravenous delivery of miR-187 encapsulated in a lipid nanoparticle (LNP) represents a fundamentally distinct, effective and pathogen-agnostic approach to correcting sepsis-induced cardiac dysfunction through modulation of cardiomyocyte inflammatory and metabolic pathways.

molecular biology↗

bioRxiv2025

SUSTAINED SYSTEMIC AND NEUROINFLAMMATION IN COGNITIVE DYSFUNCTIONAL FEMALE MICE AFTER NON-SEVERE EXPERIMENTAL MALARIA

Plasmodial infection induces systemic inflammation with great potential to contribute to the development of severe illness and lethality. It is known that the hippocampus and cortex both play a pivotal role in memory processes and are affected by the neuroinflammation associated with cerebral malaria that causes long-lasting cognitive and behavioral sequelae. Since these sequelae are also associated with the non-severe form of malaria, it is important to correlate brain morphology, particularly glial cell involvement, and neuroimmune and neuroinflammatory features with memory acquisition and consolidation processes, in this clinical presentation of malaria, the most frequent worldwide. Here, we aimed to investigate cellular and molecular neuroimmune aspects of non-severe experimental malaria-associated cognitive dysfunction. Female C57BL/6 mice were infected with Plasmodium berghei ANKA and treated with chloroquine before any clinical signs of cerebral malaria emerged. No histopathological alteration, in hematoxylin-eosin staining, or axonal damage, in Bielschowskys silver-impregnated brain sections, was observed. However, morphological alterations in GFAP+ and Iba-1+ cells suggest that: i) astrocytes in the hippocampal dentate gyrus and the cornu Ammonis 1 regions and ii) microglia in the cornu Ammonis 1 region are responding to infection. Curiously, the effect persisted only in Iba-1+ cells up to 22 days post-infection. An increase in pro-inflammatory cytokines levels and expression was observed, in both the prefrontal cortex and the hippocampus. Also, serum and spleen cytokine levels were increased at 4 days post-infection. At 22 days post-infection, infected and treated mice showed an increase in serum cytokine levels that had homeostatic levels at 155 days post-infection. This dynamic points to both an immune stimulus persistence and a cytokine autoregulation post-infection. Infected mice exhibited acquisition and consolidation memory deficits in behavioral tests early after treatment (22 days post-infection). In conclusion, in a context of sustained systemic inflammation, mild neuroinflammatory alterations of glial cells may be involved in cognitive sequelae following a single episode of non-severe experimental malaria.

immunology↗